Ischemic heart disease (IHD) is the leading cause of death in the USA and results in irreversible damage to the myocardium. Recent studies suggest that cardiac function can be restored by adding new, healthy cells such as skeletal muscle myoblasts (SKMB) or bone marrow-derived mesenchymal stem cells (MSC). Early results of cell therapy are encouraging and indicate hemodynamic improvement;however, it is unknown if cell therapy can reduce the risk of sudden cardiac death (SCO) associated with IHD. Moreover, significant safety concerns have been raised due to reports of increased arrhythmia risk. To date, several studies suggest that the ability of transplanted cells to electrically couple with host cells is an important determinant of arrhythmia risk. In addition, augmenting the natural tissue regeneration process by enhancing stem cell homing to the site of damaged myocardium may provide further benefit. In general, we hypothesize that the ability of cell therapy to reduce arrhythmia vulnerability will be determined by its ability to enhance electrophysiological viability of the infarct zone through the engraftment of viable cells that form functional electrical connections. Therefore a major goal of this proposal is to determine the electrophysiological benefit and, thus, the antiarrhythmic consequence of cell therapy for IHD, and to optimize cell therapy by enhancement of intercellular coupling and cell homing/engraftment using gene therapy. To achieve these goals, novel optical mapping techniques and a rat model of IHD will be utilized to address the following specific aims: 1) Develop and validate an optical mapping system to investigate cell therapy for SCD associated with myocardial infarction (Ml) in rat. 2) Determine the mechanisms by which cell therapy provides electrophysiological benefit or detriment in hearts with Ml. 3) Establish the antiarrhythmic or proarrhythmic mechanisms associated with cell therapy for Ml in the whole heart. 4) Determine if overexpression of connexin protein (Cx40, Cx43, and Cx45) and SDF-1 (stem cell homing factor) can significantly enhance SKMB and MSC cell therapy for SCD associated with Ml. Overall, this study will improve the understanding of the electrophysiology of cell therapy for IHD, and lay important basic groundwork for more extensive, science-based, clinical trials. The long-term goal of this study is to develop a cure for SCD associated with IHD.